4-methoxybiphenyl hydrazone derivatives

ABSTRACT

Disclosed herein is a compound having the formula:                    
     wherein R 1  is alkyl and R 2  and R 3  are independently selected aryl groups. Also disclosed is a method of making bifenazate using the compound as an intermediate.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain 4-methoxybiphenyl hydrazidederivatives useful as intermediates in the preparation ofisopropyl-2-(4methoxy-[1,1′-biphenyl]-3-yl)hydrazine carboxylate(Bifenazate).

2. Description of Related Art

Destruction by insects, acarids and nematodes presents a serious problemto agriculture. A wide variety of field crops are in need of protectionfrom nematodes, acarids, and insects, including such valuable crops assoybeans, corn, peanuts, cotton, alfalfa, rice, and tobacco. Inaddition, vegetables, such as tomatoes, potatoes, sugar beets, carrots,peas, and the like, as well as fruits, nuts, ornamentals, and seed bedcrops, such as apples, peaches, almonds, citrus fruit, and grapes mayalso require protection from the ravages of such pests.

Consequently, the development of new, more effective methods forpreparing known pesticides, including insecticides, acaricides, andnematicides represents an ongoing scientific activity. Moreparticularly, the development of improved methods for the preparation ofknown pesticides that are effective as both ovicides and larvicides areof interest.

One such pesticide is Bifenazate, which can be prepared by a six stepprocedure from 4-hydroxybiphenyl hydrazine, which is, in turn, preparedfrom a diazonium salt. This method is laborious, costly, and requirescareful attention to the sensitive key steps, i.e., the preparation andreduction of the diazonium salt.

U.S. Pat. No. 5,367,093 describes a method for the preparation of themiticidal phenylhydrazine derivative, isopropyl-2-(4methoxy-[1,1′-biphenyl]-3-yl)hydrazine carboxylate (bifenazate), using a six-stepprocedure comprising the undesirable steps of preparation and reductionof a diazoniun salt.

U.S. Pat. No. 6,093,843 discloses compounds having the formula:

wherein R is hydrogen or CO₂CH(CH₃)₂, useful as intermediates in thepreparation of the miticide bifenazate, methods for their preparation,and methods for the preparation of the bifenazate.

U.S. Pat. No.6,235,936 discloses a method for the transitionmetal-catalyzed arylation, or vinylation, of hydrazines, hydrazones, andthe like. Additionally, a strategy is provided, the cornerstone of whichis a transition metalatalyzed arylation or vinylation method, for thesynthesis of indoles, carbazoles, and the like. It is said that themethods and strategies of the invention may be utilized in standard,parallel, and combinatorial synthetic protocols. (See also the relatedWO 99/43643 and Wagaw et al., J. Am. Chem. Soc. 120(26):6621-2 (1998).)

Additionally, certain phenylhydrazine derivatives can be prepared usingthe methods described in U.S. Pat. No. 4,864,032 (amination ofGrignard); in Mitchell, J. Org. Chem. 59: 682 (1994) (amination ofelectron-rich arenes); and in Lenarsic, J. Org. Chem. 64: 2558 (1999)(by electrophilic azodicarboxylates).

The disclosures of the foregoing are incorporated herein by reference intheir entirety.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide new intermediatesuseful in the preparation of bifenazate.

It is another object of the present invention to provide a new methodfor the preparation of bifenazate.

It is another object of the present invention to prepare aryl hydrazonesof 4-alkoxybiphenyl that are useful as intermediates for the preparationof bifenazate, whereby the inefficient preparation and reduction of adiazonium salt intermediate can be avoided.

These and other objects are accomplished by means of the presentinvention, which relates to compounds (hereinafter referred to asCompound I) that are useful intermediates for the preparation ofbifenazate having the formula:

wherein R₁ is alkyl and R₂ and R₃ are independently selected arylgroups.

Thus, the present invention is directed to a compound having theformula:

wherein R₁ is alkyl and R₂ and R₃ are independently selected arylgroups.

In another aspect, the present invention is directed to a method forpreparing bifenazate comprising:

A) coupling a 3-halo-4-methoxybiphenyl, preferably3-bromo-4-methoxybiphenyl, with a diarylhydrazone in the presence of acoupling catalyst, a ligand, a first base, and a solvent at or aboveroom temperature to form a compound of the formula I:

B) treating the compound of formula I with a mixture of hydrochloricacid and ethyl acetate to give a compound of formula II:

C) converting the compound of formula II to bifenazate by reaction withan alkali metal hydroxide, preferably sodium hydroxide, followed byreaction with an isopropyl haloformate, preferably isopropylchloroformate, in the presence of a second base.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

As disclosed above, the present invention relates to compounds havingthe formula:

wherein R₁ is alkyl and R₂ and R₃ are independently selected arylgroups.

R₁ is preferably a lower alkyl, which may, if desired, be branched. Itis more preferably a lower alkyl of from one to four carbon atoms, e.g.,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ortert-butyl. Thus, OR₁ in the above formula will be an alkoxy group,preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy, or tert-butoxy. It is especially preferred that R₁ be methyland OR₁ be methoxy.

R₂ and R₃ of Compound I are independently selected aryl groups, whichmay be substituted or unsubstituted. The term “aryl” as used hereinincludes 5-, 6- and 7-membered single-ring aromatic groups that mayinclude from zero to four heteroatoms, for example, benzene, pyrrole,furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole,pyridine, pyrazine, pyridazine, pyriridine, and the like. Those arylgroups having heteroatoms in the ring structure may also be referred toas “aryl heterocycles” or “heteroaromatics”. The aromatic ring can besubstituted at one or more ring positions with such substituents as, forexample, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, nitro,alkylthio, heterocyclyl, aromatic or heteroaromatic moieties, -CF₃, -CN,or the like. The term “aryl” also includes polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings (the rings are “fused rings”) wherein at leastone of the rings is aromatic, e.g., the other cyclic rings can, ifdesired, be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, and/orheterocyclyls.

It is preferred that both R₂ and R₃ be phenyl, either or both of whichcan optionally be substituted, preferably with one or more groupsselected from the group consisting of halo, alkoxy, haloalkyl, thienyl,fluorenyl, and halofluorenyl.

The compounds employed in the practice of the present invention can beprepared as described below and as shown in Scheme 1.

3-Bromo4-methoxybiphenyl is coupled with a diarylhydrazone using asuitable coupling catalyst in the presence of a suitable ligand and abase in a suitable solvent at room or elevated temperature to formCompound I.

The coupling catalyst is preferably a transition metal catalystincluding soluble or insoluble complexes of platinum, palladium, andnickel. Nickel and palladium are particularly preferred and palladium ismost preferred. Suitable catalysts include, but are not limited to,palladium acetate, tris(dibenzylideneacetone)dipalladium, nickeldiphenylphosphinoferrocene, and the like.

The ligand is preferably a phosphine ligand that is commerciallyavailable or can be prepared by methods similar to processes known inthe art. The phosphines can, for example, be tri-tert-butylphosphine,2-(di-tert-butylphophino)biphenyl, 2,2-′(dicyclohexylphosphino)biphenyl,or a bidentate phosphine ligand, such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,1,2-bis(dimethylphosphino)ethane, 1,2-bis(diethylphosphinoethane,1,2-bis(dipropylphosphino)ethane, 1,2-bis(diisopropylphosphino)ethane,1,2-bis(dibutyl-phosphinocthane, 1,2-bis(dicyclohexylphosphino)ethane,1,3-bis(dicyclohexylphosphino)propane,1,3-bis(diiso-propylphosphino)propane,1,4-bis(diisopropylphosphino)-butane, or2,4-bis(dicyclohexylphosphino)pentane.

Bis(phosphine) ligands are particularly preferred. Suitablebis(phosphine) compounds include, but are not limited to,(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (and separateenantiomers), (±)-2,2′-bis(di-p-tolylphosphino)-1,1,′-binaphthyl (andseparate enantiomers), 1,1′-bis(diphenylphosphino)ferrocene,1,3-bis(diphenylphosphino)propane, 1,2-bis(diphenylphosphino)benzene,2,2′-bis(diphenylphosphino)diphenyl ether, and1,2-bis(diphenylphosphino)ethane.

The most preferred ligands for use in the practice of the presentinvention include 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, bis{2-(diphenylphosphino)phenyl}ether,1-(N,N-dimethylamino)-1′-(dicyclohexylphosphino)biphenyl,1,1′-bis(diphenylphosphino)ferrocene, and the like.

The base employed in the coupling reaction can, for example, be analkoxide, such as alkali metal alkoxides, e.g., sodium tert-butoxide; analkali metal or alkaline earth carbonate or phosphate (e.g. sodium,magnesium, calcium, barium, potassium carbonate or phosphate). Preferredbases for use in the practice of the present invention include sodiumt-butoxide, cesium carbonate, and potassium phosphate.

Suitable solvents include ethers, such as diethyl ether,1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuiran,and the like; halogenated solvents, such as chloroform, dichloromethane,dichloroethane, chlorobenzene, and the like; aliphatic or aromatichydrocarbon solvents, such as benzene, xylene, toluene, hexane, pentane,and the like; esters and ketones, such as ethyl acetate, acetone, and2-butanone; polar aprotic solvents, such as acetonitrile,dimethylsulfoxide, dimethylformamide, and the like; or combinations oftwo or more solvents. Toluene, dimethoxyethane, and tetrahydrofuran arepreferred.

In general, it will be desirable that the coupling reaction be run usingmild conditions that will not adversely affect the reactants, thecatalyst, or the product. The coupling reaction will usually be run attemperatures ranging from room temperature, e.g., about 20° C., to about300° C., preferably from about 200° C. to about 150° C.

Compound I can then be treated with a mixture of hydrochloric acid andethyl acetate to give hydrazine intermediate II , which can be convertedto bifenazate by reaction with sodium hydroxide followed by reactionwith isopropyl chloroformate in the presence of a base, e.g., pyridine.Compound II is an intermediate in a known method for preparingbifenazate, and the method for its conversion to bifenazate is describedin U.S. Pat. No. 5,367,093.

The advantages and the important features of the present invention willbe more apparent from the following examples.

EXAMPLE 1 Methanone, Diphenyl-,(4-Methoxy-[1,1′-biphenyl]-3-yl)hydrazone

3-Bromo-4-4-methoxybiphenyl (0.52 gram), palladium acetate (6.7 mg),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (28 mg), sodiumtert-butoxide (0.29 gram), and benzophenone hydrazone (0.43 gram) wereweighed into a reaction vessel and placed under a nitrogen atmosphere.Toluene (5 mL) was added and the mixture was heated on a steam bath for16 hours, then at 120° C. for 4 hours. The mixture was cooled, dilutedwith ethyl acetate (15 ml), washed with water, dried over sodiumsulfate, and concentrated to give Compound I, methanone, diphenyl-,(methoxy-{1,1′-biphenyl}-3-yl)hydrazone, (0.61 gram) as a beige solid.¹H nmr (CDCl₃)δ8.0-6.8 (m, 19 H), 3.6 (s, s H). EIMS m/z 378.

Other species within the scope of Compound I were prepared. Their namesand 1H NMR data are shown in Table 1.

TABLE 1 1H NMR Data {chemical shift Name (multiplicity, integration)}Methanone, diphenyl-, (4-methoxy-{1, 8.0-6.8(m, 19H), 3.6(s, 3H)1′-biphenyl}-3-yl)hydrazone Methanone, bis(4-methoxyphenyl)-, 8.0-6.8(m,18H), 3.9(s, 3H), (4-methoxy-{1,1′-biphenyl}-3- 3.8(s, 3H), 3.7(s, 3H)yl)hydrazone Methanone, bis(3-(trifluoromethyl) 8.2-6.8(m, 18H), 3.8(s,3H) phenyl}-, (4-methoxy-{1,1′- biphenyl}-3-yl)hydrazone9H-fluoren-9-one, (4-methoxy- 9.4(s, 1H), 8.0-7.0(m, 16H),{1,1′-biphenyl}-3-yl)hydrazone 4.0(s, 3H) Methanone,(4-fluorophenyl)-8.0-6.8(m, 16H), 3.9(s, 1H), 2-thienyl-, (4-methoxy-{1,1′- 3.8(s, 2H)biphenyl}-3-yl)hydrazone 9H-fluoren-9-one, 2,7-dichloro-, 10.0(s, 1H),8.0-7.0(m, 14H), (4-methoxy-{1,1′-biphenyl}- 4.0(s, 3H) 3-yl)hydrazone

The structural formula of methanone, diphenyl-,(4methoxy-{1,1′-biphenyl}-3-yl)hydrazone is:

The structural formula of methanone, bis(4-methoxyphenyl)-,(4-methoxy-{1,1′-biphenyl}-3-yl)hydrazone is:

The structural formula of methanone, bis{3-(trifluoromethyl)phenyl}-,(4-methoxy-{1,1′-biphenyl}-3-yl)hydrazone is:

The structural formula of 9H-fluoren-9one,(4-methoxy-{1,1′-biphenyl}-3-yl)hydrazone is:

The structural formula of methanone,(4-fluorophenyl)-2-thienyl-,(4-methoxy-{1,1′biphenyl}-3-yl)hydrazone is:

The structural formula of 9H-fluoren-9-one,2,7-dichloro-,(4-methoxy-{1,1-biphenyl}-3-yl)hydrazone is:

EXAMPLE 2 Bifenazate

To a suspension of Compound I (0.6 gram) in ethyl acetate (3 mL) wasadded 0.5 mL of concentrated hydrochloric acid. The mixture was stirredat room temperature for 16 hours and then heated to reflux for 1.5hours. The mixture was cooled, filtered, and washed with ethyl acetateto give 0.29 gram of an off-white solid. This material was stirred in 2M NaOH (aq) (5 mL) for 20 minutes and then ethyl acetate (10 mL) wasadded and stirring was continued for 10 minutes. More ethyl acetate wasadded (15 mL) and the phases separated. The ethyl acetate phase waswashed with brine, dried over sodium sulfate and concentrated. Theresidue was dissolved in toluene (3 mL) and cooled in ice. Pyridine(0.19 mL) was added followed by a one molar solution of isopropylchloroformate in toluene (1.3 mL). The mixture was stirred for 30minutes and then extracted with water and concentrated. The residue wasthen co-distilled with toluene to give bifenazate (0.32 gram) which wasconfirmed by comparison to an authentic sample.

In view of the many changes and modifications that can be made withoutdeparting from principles underlying the invention, reference should bemade to the appended claims for an understanding of the scope of theprotection to be afforded the invention.

What is claimed is:
 1. A compound having the formula:

wherein R₁ is alkyl and R₂ and R₃ are independently selected arylgroups.
 2. The compound of claim 1 wherein R₁ is a lower alkyl of fromone to four carbon atoms.
 3. The compound of claim 2 wherein R₁ ismethyl.
 4. The compound of claim 1 wherein at least one of R₂ anid R₁ isselected from the group consisting of 5-, 6- and 7-membered single-ringaromatic groups having from zero to four heteroatoms.
 5. The compound ofclaim 4 wherein at least one of R₂ anid R₃ is selected from the groupconsisting of benzene, pyrrole, furan, thiophene, imidazole, oxazole,thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, andpyrimidine.
 6. The compound of claim 3 wherein at least one of R₂ and R₃is selected from the group consisting of 5-, 6- and 7-memberedsingle-ring aromatic groups having from zero to four heteroatoms.
 7. Thecompound of claim 6 wherein at least one of R₂ and R₃ is selected fromthe group consisting of benzene, pyrrole, furan, thiophene, inidazole,oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine,and pyrimidine.
 8. The compound of claim 1 wherein at least one of R₂and R₃, or R₂ and R₃ taken together, comprise a polycyclic ring systemhaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings and wherein at least one of the rings isaromatic.
 9. The compound of claim 3 wherein at least one of R₂ and R₃,or R₂ and R₃ taken together, comprise a polycyclic ring system havingtwo or more cyclic rings in which two or more carbons are common to twoadjoining rings and wherein at least one of the rings is aromatic. 10.The compound of claim 1 wherein said compound is selected from the groupconsisting of methanone, diphenyl-,(4-methoxy-{1,1′-biphenyl}-3-yl)hydrazone; methanone,bis(4methoxyphenyl)-, (4-methoxy-{1,1′-biphenyl}-3-yl)hydrazone;methanone, bis{3-(trifluoromethyl)phenyl}-,(4-methoxy-{1,1′-biphenyl}-3-yl)hydrazone; 9H-fluoren-9-one,(4-methoxy-{1,1′-biphenyl}-3-yl)hydrazone; methanone,(4-fluorophenyl)-2-thienyl-, (4-methoxy-{1,1′-biphenyl}-3-yl)hydrazone;and 9H-fluoren-9one, 2,7-dichloro-,(4-methoxy-{1,1′-biphenyl}-3-yl)hydrazone.
 11. A method for preparingbifenazate comprising: A) coupling a 3-halo-4-methoxybiphenyl with adiarylhydrazone in the presence of a coupling catalyst, a ligand, afirst base, and a solvent at or above room temperature to form acompound of the formula I;

(B) treating the compound of formula I with a mixture of hydrochloricacid and ethyl acetate to give a compound of formula II:

and C) converting the compound of formula II to bifenazate by reactionwith an alkali metal hydroxide followed by reaction with isopropylhaloformate in the presence of a second base.
 12. The method of claim 11wherein at least one of R₂ and R₃ is selected from the group consistingof 5-, 6- and 7-membered single-ring aromatic groups having from zero tofour heteroatoms.
 13. The method of claim 11 wherein at least one of R₂and R₃ is selected from the group consisting of benzene, pyrrole, furan,thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine,pyrazine, pyridazine, and pyrimidine.
 14. The method of claim 11 whereinat least one of R₂ and R₃, or R₂ and R₃ taken together, comprise apolycyclic ring system having two or more cyclic rings in which two ormore carbons are common to two adjoining rings and wherein at least oneof the rings is aromatic.
 15. The method of claim 11 wherein thecompound of formula I is selected from the group consisting ofmethanone, diphenyl-, (4methoxy-{1,1′-biphenyl}-3-yl)hydrazone;methanone, bis(4-methoxyphenyl)-,(4-methoxy-{1,1′-biphenyl}-3-yl)hydrazone; methanone,bis{3-(trifluoromethyl)phenyl}-,(4-methoxy-{1,1′-biphenyl}-3-yl)hydrazone; 9H-fluoren-9-one,(4-methoxy-{1,1′-biphenyl}-3-yl)hydrazone; methanone,(4-fluorophenyl)-2-thienyl-, (4-methoxy-{1,1′-biphenyl}-3-yl)hydrazone;and 9H-fluoren-9-one, 2,7-dichloro-,(4-methoxy-{1,1′-biphenyl}-3-yl)hydrazone.
 16. The method of claim 11wherein the coupling catalyst is a transition metal catalyst.
 17. Themethod of claim 16 wherein the transition metal catalyst is selectedfrom the group consisting of soluble and insoluble complexes ofplatinum, palladium, and nickel.
 18. The method of claim 11 wherein theligand is a phosphine ligand.
 19. The method of claim 18 wherein thephosphine ligand is selected from the group consisting oftri-tert-butylphosphine, 2-(di-tert-butylphophino)biphenyl,2-(dicyclohexylphosphino)biphenyl, bidentate phosphine ligands, andbis(phosphine) ligands.
 20. The method of claim 11 wherein the firstbase is selected from the group consisting of alkoxides, alkali metalcarbonates, alkali metal phosphates, alkaline earth carbonates, andalkaline earth phosphates.
 21. The method of claim 11 wherein thesolvent is selected from the group consisting of ethers, halogenatedsolvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents,esters, and ketones, polar aprotic solvents, or combinations thereof.22. The method of claim 21 wherein the solvent is selected from thegroup consisting of toluene, dimethoxyethane, and tetrahydrofuran. 23.The method of claim 11 wherein the second base is pyridine.